Researchers have collected vast quantities of data to determine how genetic variation between humans determines who develops depression, schizophrenia, Parkinson’s disease and many other brain disorders.
Genes are often the cause when people develop mental disorders such as depression or schizophrenia.
However, although researchers for many years have been mapping the genetic differences between humans that can be associated with various nervous system and mental disorders, these major genetic studies have not yet resulted in deeper understanding of the biological mechanisms.
Researchers can see that some genes are associated with developing Parkinson’s disease, for example. But then what?
Now, however, researchers have published a new study that comes not just one but two steps closer to understanding the biology of how genetic variation can lead to a dysfunctional psyche.
“For many years, we researchers have conducted many genome-wide association studies that have found associations between people’s genetic variants and the development of brain disorders. This is really good, because it has provided us with considerable data, but so far it has not given us the biological understanding we had hoped for. In this study, we linked the data from numerous genome-wide association studies to help us understand how genetic variants can cause diseases,” explains a researcher behind the new study, Thomas Folkmann Hansen, Associate Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen and Senior Research Manager, Danish Headache Center, Rigshospitalet, Glostrup, Denmark.
The research, which was carried out in collaboration with Karolinska Institutet in Stockholm, Sweden, has been published in Nature Genetics.
Understanding the effects of genetic variation
The background for the new study is the wealth of data researchers have collected through extensive genome-wide association studies.
Genome-wide association studies are essentially genetic studies in which the researchers compare the expression of genes among people with, for example, Parkinson’s disease to that of healthy people.
This enable researchers to determine which genes and which genetic variants are involved when the disease develops.
Specifically, researchers have previously identified 49 genes as being associated to a greater or lesser degree with Parkinson’s disease. The risk of disease developing increases when these genes function incorrectly.
“This tells us which genes are involved, but it does not determine how the genes affect the risk of developing disease. In which tissues are they affected? In which cells are they affected? Knowing this is important to enable us to use the information from the genome-wide association studies to advance our knowledge of the disease and ultimately develop medicine against it,” says Thomas Folkmann Hansen.
Gene mutations affect specific cells in Parkinson’s disease
In the new meta-analysis, the researchers conducted a new genome-wide association study of Parkinson’s disease in which they searched for correlations between genetic variants and the risk of developing the disease but also conducted in-depth single-cell expression studies of individual tissues and cells to determine where in the body and brain the genes are active.
Specifically, the researchers used mice to examine the individual cells in each given tissue, to analyse whether the genes identified in the genome-wide association studies were expressed in the individual cell – and whether they were active or just dormant.
The genome-wide association study revealed that not just 49 but 61 genes are associated with an increased risk of developing Parkinson's disease.
Subsequently, the researchers found that the genes associated with the risk of developing Parkinson’s disease are especially active in some very specific cells in the brain.
“For Parkinson’s disease, the genes we found in the study are especially active in cells with many dopamine receptors on the cell surface. For example, this applies to oligodendrocytes, which are involved in the brain’s immune system. The realization means that more targeted clinical treatment studies involving people with Parkinson’s disease can be conducted in the future,” explains Thomas Folkmann Hansen.
Underpinning a controversial theory
The fact that some specific cells in the brain are affected during the development of Parkinson's disease is not surprising, says Thomas Folkmann Hansen, but the discovery still contains some quite interesting perspectives.
Some researchers have proposed the controversial theory that Parkinson’s disease may be caused by an infection that, in the worst case, can affect the brain.
In the new study, the researchers at least conclude that they cannot reject this hypothesis because the study precisely suggests the immune cells as being involved in the risk of developing disease.
“I am not an expert in Parkinson’s disease but rather migraines and headaches. Nevertheless, we do find that some immune cells in the brain are affected. This seems particularly true for the cells with many dopamine receptors on the surface, and thus, these findings support the infection theory to some degree,” says Thomas Folkmann Hansen.
Data from 26 disorders
The study examined other aspects than Parkinson’s disease.
The researchers conducted the genome-wide association studies on Parkinson’s disease and then obtained summary statistics from external sources covering 17 other brain disorders and eight complex traits not rooted in the central nervous system.
This means that, for 18 brain disorders, including Parkinson’s disease, depression, neuroticism, autism, Alzheimer’s disease, bipolar disorder and migraine, they now know which tissues and cells are associated with the genetic variants related to the diseases.
The researchers also investigated intelligence, body mass index, type 2 diabetes and the time of first menstruation to validate that nervous system diseases are not associated with other factors that are not related to brain disorders.
“The data show that the genes involved in the risk of developing various brain disorders differ from the genes and cells from non-brain-related tissues and cell types and are also expressed in different cell types in the brain. Of course, some cell types overlap, but then the gene variants are different,” explains Thomas Folkmann Hansen.
Can lead to the development of more targeted drugs
According to Thomas Folkmann Hansen, the study can be used to advance researchers’ knowledge on the various diseases, so that the researchers can better understand how genetic variation can lead to an increased risk of developing the diseases.
This knowledge can have great basic scientific value but can also have practical applications.
The new knowledge will enable drug developers to develop drugs to target not just the diseases as a whole but the specific cells in which the genes and thus cell functions are disordered.
“The study strengthens our understanding of the biological mechanisms, and we need to understand these to understand the diseases themselves and to provide optimal treatment,” says Thomas Folkmann Hansen.
“Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease” has been published in Nature Genetics. Co-author Thomas Folkmann Hansen is employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
